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F.D.A. Pulls a Drug, And Patients Despair

In November, as soon as he learned that the drug Lotronex was being withdrawn from the market, Corey Miller, who had been taking it for about eight months, began stockpiling it. He persuaded a doctor to write an extra prescription, and went to 20 drugstores in search of the recalled pills.

Mr. Miller, a 30-year-old architect in Atlanta, knew that Lotronex had caused serious side effects in some patients and had been linked to several deaths. But he had suffered no ill effects. On the contrary, Lotronex was the only drug that had ever helped him, stopping the severe abdominal pain and diarrhea caused by an illness called irritable bowel syndrome.

''It was a miracle medicine for me,'' he said.

Lotronex was taken off the market on Nov. 28, less than 10 months after being approved by the Food and Drug Administration. About 300,000 people had taken it. It was withdrawn because about 70 patients had developed severe constipation or ischemic colitis, a lack of blood flow to the colon. Some needed surgery, including one woman who had to have her entire colon removed. There were five deaths, including three possibly linked to the drug. Nonetheless, several thousand patients have contacted the F.D.A. since the recall, wanting Lotronex back. A spokesman for the agency said that the demand for Lotronex was higher than that for any other recalled drug, and that officials were willing to consider bringing the drug back, though in a limited way. On Jan. 23, officials from the F.D.A. and the drug's manufacturer, GlaxoSmithKline, met to discuss Lotronex, but neither side would disclose what took place.

The rise and fall -- and possible resurrection -- of Lotronex highlights a longstanding problem facing the F.D.A. and pharmaceutical companies: what to do when a useful drug turns out to have significant side effects, particularly when the problems do not become apparent until after the drug is approved.

The problem has intensified in recent years because the F.D.A., given increased financing and ordered by Congress in 1992 to speed up the evaluation process, is approving new drugs faster than in the past. The number of withdrawals has grown, in part because more drugs are being approved. Three drugs were taken off the market in 1999, and 10 have been withdrawn since 1997.

Critics of the industry and the F.D.A. say the agency has acted hastily and approved too many unsafe drugs that have injured or killed patients. But the agency says the percentage of drugs recalled has been relatively steady for the past 20 years, averaging under 3 percent of the drugs approved.

Once a drug reaches the market, aggressive promotion to doctors and advertising to consumers often lead to rapid growth in sales, so that, as in the case of Lotronex, hundreds of thousands of people are taking a new drug just months after its approval.

When serious side effects occur, especially with drugs being used on such an enormous scale, consumer advocates like Dr. Sidney Wolfe, who directs the Public Citizen Health Research Group in Washington, say that the only way to prevent further harm to patients is to get the drug off the market as quickly as possible. The group sought to have Lotronex banned, arguing that it made no sense to use a drug with potentially life-threatening side effects for a disease like irritable bowel syndrome, which is debilitating but does not kill people.

But pulling a product off the market may in effect punish patients who were helped by the drug. And since pharmaceutical companies spend hundreds of millions of dollars to bring a drug to market, withdrawals have a harsh financial impact as well.

The patient uprising over Lotronex is an odd turnabout. Usually, if the F.D.A. comes under fire from consumers, it is for having approved problematic drugs in the first place, not for taking them away. But Lotronex was the first drug made specifically to treat chronic diarrhea caused by irritable bowel syndrome, and these patients and their doctors say there is no other drug for them to switch to, no other effective treatment for their condition. While the illness is not fatal, many patients say the sudden attacks of diarrhea ruin their lives, and they want to take their chances with the drug.

A spokesman for the F.D.A. said the appeals from patients seemed to be personal rather than form letters or scripted phone calls.

''People are talking about serious life issues such as being able to keep a job and function on a daily basis, or just go out of their house,'' said Jason Brodsky, a spokesman for the agency. ''Their lives were changed by the medication.''

Dr. Victor Raczkowski, as deputy director of the F.D.A. office that evaluates gastrointestinal drugs, was involved in both approving Lotronex and withdrawing it. ''The pharmaceutical industry and the F.D.A. need better sets of tools to handle safety issues that might come up once a drug is approved,'' he said. ''This is relatively new territory for the industry and the F.D.A.''

When a new drug is marketed, side effects are virtually inevitable, and they are sometimes more severe or more common than when the drug was being tested. An F.D.A. report in 1999 said side effects can emerge after marketing because far more people use the drug than in preliminary studies, enough to let uncommon problems show up. They often take the drug for longer periods than those in studies as well.

Some researchers have urged that new drugs be phased in more slowly, prescribed at first only by specialists and only for certain types of patients, to allow time for side effects to be detected and changes made before the drug is in the hands of hundreds of thousands of people.

The F.D.A. report noted that side effects also crop up after marketing because patients in the real world are different from those in studies: they may include children, who in the past were rarely studied, or they may be older and sicker, sometimes with multiple illnesses being treated by different drugs, which may interact with the new medication. Older people are also more sensitive to drugs than younger ones, and standard doses may be too high for them.

In addition, doctors in private practice and their patients may not stick as closely to directions as those participating in studies. As a result, people who should not take a new drug may get it anyway. The F.D.A. report stated that more than half of all side effects could be avoided if drugs were used properly.

Doctors' and patients' failure to follow directions may have contributed to problems in recent withdrawals like those of the diabetes drug Rezulin and the painkiller Duract. Rezulin was withdrawn because it caused liver failure in some patients. The potential for liver trouble emerged after the drug was marketed, and its labeling was changed to instruct patients and doctors that regular blood tests were needed to monitor their liver function, so that patients could stop the drug if abnormalities occurred. Surveys showed that few got the tests.

Duract, which also caused liver failure, was not supposed to be taken for more than 10 days, but some patients did take it for a longer time, including those whose livers failed.

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In the case of Lotronex, Dr. Raczkowski said that while many patients with complications had used the drug incorrectly, many others and their doctors had followed directions to the letter. And, he said, the existence of severe side effects even in patients who used the drug properly convinced the F.D.A. that it had to act.

Whatever the cause, serious side effects cannot be ignored, especially in a drug being taken by hundreds of thousands of people.

''It's hard to work through that in a crisis situation,'' Dr. Raczkowski said.

Lotronex was approved in February 2000 for women with chronic diarrhea caused by irritable bowel syndrome. The bowel disorder can also cause constipation, but Lotronex was not supposed to be prescribed for patients with that form of the disease. The drug eases abdominal pain and diarrhea by acting on nerves in the gastrointestinal tract. The approval was limited to women because preliminary studies had not found a benefit in men. Nonetheless, doctors were free to prescribe the drug ''off-label'' to men, and many did. The potential market for Lotronex was enormous: about 15 percent of Americans have irritable bowel syndrome.

When problems were reported within a few months, the F.D.A. responded in August by requiring that the manufacturer attach to each bottle of pills a pamphlet describing the risks, and warning patients of danger signs to watch out for.

But labeling changes may not work. A report published in December in the Journal of the American Medical Association about another drug with serious side effects noted that changing the directions or warnings did no good. Doctors went on prescribing it incorrectly anyway.

As reports of side effects from Lotronex mounted, Public Citizen embarked on a campaign against the drug and petitioned the F.D.A. to ban it. The group insisted that irritable bowel syndrome was not a serious enough disease to warrant the risks posed by Lotronex. Many patients were incensed, and they blame Public Citizen for the drug's ultimate withdrawal.

Richard Fireman, a Lotronex user in Chicago who communicates with other patients via the Internet, said: ''Somebody online said they wished they could give Dr. Wolfe irritable bowel syndrome, so he'd know what he was talking about. I feel the same way. I've never been so angry.''

But Dr. Wolfe said: ''I've been contacted by relatives of people who died or people who had emergency surgery and had big chunks of their intestines removed, and who said thank you for getting this off the market.''

At meetings with Glaxo Wellcome in the fall, (the company became GlaxoSmithKline in December, after a merger), F.D.A. officials suggested ways to keep the drug on the market, but limit access to it to minimize risks and track problems more effectively. But the company rejected the suggestions.

Ramona Dubose, a spokeswoman for GlaxoSmithKline, said: ''What they were proposing was that Lotronex would only be available through gastroenterologists who had been certified by Glaxo to prescribe the drug. Then, we as a company were responsible for monitoring every prescription written, and if any physician wrote off-label, they would be kicked out of the program, which put us in the untenable position of policing physicians. We would have to supply the drug. It would no longer go through pharmacies.''

The ban on off-label prescribing, Ms. Dubose pointed out, would make it impossible for men to get Lotronex.

''Look at the safety profile of Lotronex,'' she said. ''It doesn't make any sense to us to put it under such restrictions. We felt like we had no option but to withdraw the drug.''

But Dr. Raczkowski said there were still other options, via two main routes. The one that he called the most expedient, with the potential to restore the drug to some patients within weeks, would be to classify it as an investigational new drug, the category given to drugs that are experimental and still under study.

Patients could then get the drug by meeting certain medical criteria and signing up for programs that would be run like studies and would provide data to the F.D.A. Lotronex might be reserved for patients with the severest symptoms, who had already been helped by the drug, because in them the benefits would most likely outweigh the risks, Dr. Raczkowski said. The programs would have to include safety monitoring and reporting, and be approved by the F.D.A. and by ethics panels at hospitals or clinics. Patients would have to sign consent forms that explained the risks and benefits.

Another drug taken off the market last year, Propulsid, is being provided to some patients in this kind of program, Dr. Raczkowski said. That drug, used to treat gastroesophageal reflux, was withdrawn because it caused heart problems in some patients. But many people took it without ill effect, and for some, it was the only thing that worked, and those patients are being allowed to continue using it.

But the investigational status has serious drawbacks, Dr. Raczkowski said. The monitoring and reporting are cumbersome. More important, drug companies must provide investigational drugs for free, or in some cases at cost.

''In terms of longer term access, probably the better solution is continued marketing under conditions that both the drug company and the F.D.A. would agree to,'' he said.

But he declined to reveal what those conditions might be, saying, ''It's for the F.D.A. and the company to sit down and discuss, outside of the public eye.''

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A version of this article appears in print on January 30, 2001, on Page F00001 of the National edition with the headline: F.D.A. Pulls a Drug, And Patients Despair. Order Reprints|Today's Paper|Subscribe